Method for preparing tyrosine kinase inhibitor and derivative thereof

ABSTRACT

The present invention relates to a method for preparing a tyrosine kinase inhibitor and a derivative thereof. The present method has a short synthesis route, low costs, easy operation, and is suitable for large-scale production.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Section 371 of International Application No.PCT/CN2017/082164, filed Apr. 27, 2017, which was published in theChinese language on Nov. 2, 2017, under International Publication No. WO2017/186140 A1, which claims priority under 35 U.S.C. § 119(b) toChinese Application No. 201610274566.2, filed Apr. 28, 2016, thedisclosures of which are incorporated herein by reference in theirentirety.

FIELD OF THE INVENTION

The present invention relates to a method for preparing a tyrosinekinase inhibitor and a derivative thereof, and also relates to a newintermediate and a method for preparing the same.

BACKGROUND OF THE INVENTION

In recent years, cancer mortality in our country has increasedobviously. The mortality of malignant tumors in urban residents is about100-200/100,000. People's lives and quality of life are seriouslythreatened by cancer. With regard to malignant tumor proliferation, thechemotherapy with conventional chemotherapy drugs or the radiotherapy ishighly toxic and has poor specificity. Therefore, it is a challengingand significant subject nowadays in the life sciences to search foranti-tumor drugs with high efficacy and low toxicity. Receptor tyrosinekinase is a class of transmembrane proteins involved in signaltransduction. It is expressed in a variety of cells, for regulating cellgrowth, differentiation and neovascularization. Studies have shown thatmore than 50% of the proto-oncogene and oncogene products have tyrosinekinase activity, the abnormal expression of which causes tumorigenesis,and is also closely related to tumor invasion and metastasis, tumorneovascularization, and chemotherapy resistance of tumors. Tyrosinekinase inhibitors have been commercially available since 2001, and havebecome a new class of anticancer drugs that rise rapidly.

A number of tyrosine kinase inhibitors, such as Canertinib (CI-1033),BIBW-2992, Neratinib (HKI-272) and Pelitinib (EKB-569), have beendisclosed in the prior art. Among them, Canertinib is the first to enterclinical trials, which was found to cause thrombocytopenia in phase IIclinical trials. Therefore, research on Canertinib has been terminated.However, irreversible pan-ErbB inhibitors, such as PF-00299804 obtainedby modification of Canertinib, have been developed continuously.Pre-clinical trials have demonstrated that PF-00299804 can inhibit theEGFR mutant T790M and the wild-type thereof, as well as HER-2 resistantto Gefitinib.

BIBW2992 is a novel drug developed by Pfizer as a first-line drug forthe treatment of advanced non-small cell lung cancer (NSCLC).

Neratinib is a small molecule tyrosine kinase inhibitor developed byPuma Biotechnology under the license of Wyeth and Pfizer, and is used inpatients with solid tumors, metastatic breast cancer, and non-small celllung cancer who have been treated with Herceptin.

WO2011029265 discloses an effective tyrosine kinase inhibitor and apreparation method thereof, its chemical name is(R,E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3-cyano-7-ethoxyquinoline-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide,and its structure is as shown in formula I,

This compound has obvious pharmacodynamic advantages. CN102933574Adiscloses a dimaleate salt of the compound, which has improvedphysicochemical properties, pharmacokinetic properties, andbioavailability.

The method for preparing the compound of formula I disclosed in theprior art is as follows:

-   6-amino-4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-7-ethoxy    -quinoline-3-carbon itrile is reacted with diethyl phosphonoacetate,    followed by reaction with 1-methylpyrrolidine-2-carbaldehyde to    obtain the compound of formula I. The method has disadvantages such    as complicated operation, high cost, low yield, low safety, and    difficulty in scaling up the production.

SUMMARY OF THE INVENTION

In order to overcome the deficiencies of the prior art, the object ofthe present invention is to provide a method for synthesizing a tyrosinekinase inhibitor and a derivative thereof, which is more suitable forindustrial production.

In one aspect, the present invention provides a compound of formula VI,

wherein R₂ is selected from the group consisting of hydrogen, an aminoprotecting group, cycloalkyl, cycloalkenyl, alkyl, alkenyl, alkynyl,aralkyl, and substituted or unsubstituted aryl or heteroaryl;

R is selected from the group consisting of hydroxy, —OR_(a), andhalogen; and

R_(a) is selected from the group consisting of alkyl, aryl, andalkylaryl, wherein the alkyl, aryl, and alkylaryl are each optionallysubstituted by a substituent.

In another aspect, the invention provides a method for preparing acompound of formula II or a pharmaceutically acceptable salt thereof,

wherein:

R is selected from the group consisting of hydroxy, —OR_(a), andhalogen;

R_(a) is selected from the group consisting of alkyl, aryl, andalkylaryl, wherein the alkyl, aryl, and alkylaryl are each optionallysubstituted by a substituent;

R₁ is selected from the group consisting of hydrogen, cycloalkyl,cycloalkenyl, alkyl, alkenyl, alkynyl, aralkyl, and substituted orunsubstituted aryl or heteroaryl;

R₂ and R₃ are each independently hydrogen, an amino protecting group,cycloalkyl, cycloalkenyl, alkyl, alkenyl, alkynyl, aralkyl, or asubstituted or unsubstituted aryl or heteroaryl group, or R₁ and R₃together with the nitrogen to which R₃ is attached form anitrogen-containing heteroaryl or heterocyclyl, or R₂ and R₃ togetherwith the nitrogen to which R₃ is attached form a nitrogen-containingheteroaryl or heterocyclyl;

A is selected from the group consisting of a carbon atom and a nitrogenatom;

when A is a carbon atom, R₅ is selected from the group consisting of ahydrogen atom and alkyl, wherein the alkyl is optionally substituted byone or more substituents selected from the group consisting of halogenand alkoxy, and R₆ is cyano;

when A is a nitrogen atom, R₅ is selected from the group consisting of ahydrogen atom and alkyl, wherein the alkyl is optionally substituted byone or more substituents selected from the group consisting of halogenand alkoxy, and R₆ is unsubstituted;

R₄ has the following structure:

wherein:

D is selected from the group consisting of aryl and heteroaryl, whereinthe aryl and heteroaryl are each independently and optionallysubstituted by one or more substituents selected from the groupconsisting of halogen, alkyl and trifluoromethyl;

T is selected from the group consisting of —(CH₂)r-, —O(CH₂)r-,—NH(CH₂)r-, and —S(CH₂)r;

L is selected from the group consisting of aryl and heteroaryl, whereinthe aryl and heteroaryl are each independently and optionallysubstituted by one or more halogen or alkyl; and

r is 0, 1 or 2,

the method comprises a step of reacting a compound of formula IV with acompound of formula III.

The compound of formula IV can also be introduced into the reaction inthe form of an acid addition salt thereof, for example, a hydrochloridesalt and the like, to facilitate the feeding process.

In a preferred embodiment of the present invention, R is hydroxy, andthe compound of formula IV can be reacted with the compound of formulaIII in the presence of a condensing agent, wherein the condensing agentcan be a conventional condensing agent, for example, one or more of DCC,EDC, BOP, HBTU, and EEDQ, preferably EEDQ.

The solvent for the reaction can be one or more of pyridine, quinoline,acetonitrile,

N-methylpyrrolidone, dichloromethane, ethyl acetate, tetrahydrofuran,N,N-dimethylformamide, and N,N-dimethylacetamide, preferablyN-methylpyrrolidone. The reaction is preferably carried out at 20-30° C.

In another preferred embodiment of the present invention, R is ahalogen, preferably chlorine. The method also comprises a step ofreacting a compound of formula V with an acyl halogenating reagent toobtain a compound of formula IV.

The acyl halogenating reagent can be one or more of oxalyl chloride,phosphorus halide, thionyl halide, and triphenylphosphine halide. Thesolvent for the two reactions can be one or more of pyridine, quinoline,acetonitrile, N-methylpyrrolidone, dichloromethane, ethyl acetate,tetrahydrofuran, N,N-dimethylformamide, and N,N-dimethylacetamide,preferably N-methylpyrrolidone.

Further, the compound of formula II can be a compound of formula I, thecompound of formula III can be a compound of formula VII, and thecompound of formula IV can be a compound of formula VI,

wherein R₂ is selected from the group consisting of hydrogen, an aminoprotecting group, cycloalkyl, cycloalkenyl, alkyl, alkenyl, alkynyl,aralkyl, and substituted or unsubstituted aryl or heteroaryl;

R is selected from the group consisting of hydroxy, —OR_(a), andhalogen; and

R_(a) is selected from the group consisting of alkyl, aryl, andalkylaryl, wherein the alkyl, aryl, and alkylaryl are each optionallysubstituted by a substituent.

The pharmaceutically acceptable salt of the compound of formula I can bep-toluenesulfonate salt, methanesulfonate salt, maleate salt, succinatesalt or malate salt, preferably maleate salt, and more preferablydimaleate salt. The above salts of the compound of formula I can beprepared by a method disclosed in the prior art (for exampleCN102933574A).

Further, the compound of formula II can be Neratinib, the compound offormula III can be a compound of formula VII, and the compound offormula IV can be a compound of formula IX,

wherein R is selected from the group consisting of hydroxy, —OR_(a), andhalogen;

R_(a) is selected from the group consisting of alkyl, aryl, andalkylaryl, wherein the alkyl, aryl, and alkylaryl are each optionallysubstituted by a substituent; and

R₂ and R₃ are each independently hydrogen, an amino protecting group,cycloalkyl, cycloalkenyl, alkyl, alkenyl, alkynyl, aralkyl, andsubstituted or unsubstituted aryl or heteroaryl.

In another aspect, the present invention provides a method for preparinga compound of formula VI, comprising a Wittig-Horner reaction between acompound of formula VIII and phosphoryl carboxylate to obtain a compoundof formula X,

wherein R₂ is selected from the group consisting of hydrogen, an aminoprotecting group, cycloalkyl, cycloalkenyl, alkyl, alkenyl, alkynyl,aralkyl, and substituted or unsubstituted aryl or heteroaryl;

R is selected from the group consisting of hydroxy, —OR_(a), andhalogen; and

R_(a) is selected from the group consisting of alkyl, aryl, andalkylaryl, wherein the alkyl, aryl, and alkylaryl are each optionallysubstituted by a substituent, and the phosphoryl carboxylate ispreferably triethyl phosphonoacetate.

In a preferred embodiment of the present invention, R is hydroxy orhalogen, the method also comprises a step of hydrolyzing the compound offormula X in the presence of an alkaline medium, the alkaline medium isone or more selected from the group consisting of Et₃N, DBU, TMG Py,DIPEA, K₂CO₃, KHCO₃, Na₂CO₃, NaHCO₃, KOH, NaOH, NaOMe, NaOEt, NaOtBu,and NaH, preferably KOH.

Further, when R is chlorine, the method also comprises a step ofreacting the product obtained by hydrolysis in the previous step with anacyl halogenating reagent, the acyl halogenating reagent is one or moreselected from the group consisting of oxalyl chloride and thionylchloride.

The method for preparing a tyrosine kinase inhibitor and a derivativethereof according to the present invention has the advantages of safeand simple operation, high optical purity of the product, safe reactionreagent, milder reaction conditions, lower cost, and is suitable forindustrial production. The reaction results are superior to the priorart, with significant social and economic benefits. The process ofcondensation reaction using a condensing agent can be carried out atroom temperature, column chromatography is avoided which simplifies thepost-treatment process, the reaction is easy to monitor, the feedingamount is optimized to reduce the cost, the reaction is stable and easyto reproduce, and the like, therefore, the method is more suitable forindustrial scale production.

“Amino protecting group” refers to a suitable group known in the art forprotecting an amino group, such as the amino protecting groups disclosedin the document (“Protective Groups in Organic Synthesis”, 5^(Th). Ed.T. W. Greene & P. G M. Wuts). Preferably, the amino protecting group canbe (C₁₋₁₀ alkyl or aryl)acyl, for example, formyl, acetyl, benzoyl andthe like; it can be (C₁₋₆ alkyl or C₆₋₁₀ aryl)sulfonyl; or it can alsobe (C₁₋₆ alkoxy or C₆₋₁₀ aryloxy)carbonyl, Boc or Cbz.

“Alkyl” refers to a linear or branched saturated aliphatic hydrocarbongroup having 1 to 20 carbon atoms, preferably an alkyl group having 1 to10 carbon atoms, for example, methyl, ethyl, propyl, 2-propyl, n-butyl,isobutyl, tert-butyl, pentyl and the like, and more preferably a loweralkyl group having 1 to 6 carbon atoms, for example methyl, ethyl,propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl, heptyl and thelike. The alkyl can be substituted or unsubstituted. When the alkyl issubstituted, the substituent is preferably one or more groupsindependently selected from the group consisting of alkoxy, halogen,hydroxy, nitro, cyano, cycloalkyl, heterocyclyl , aryl, heteroaryl, andcarbonyl.

“Aryl” refers to a 6 to 14-membered all-carbon monocyclic ring orpolycyclic fused ring (i.e. each ring in the system shares an adjacentpair of carbon atoms with another ring in the system) having aconjugated π-electron system, preferably 6 to 10-membered aryl, morepreferably phenyl and naphthyl, and most preferably phenyl. The aryl canbe substituted or unsubstituted. When the aryl is substituted, thesubstituent is preferably one or more groups independently selected fromthe group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio,alkylamino, halogen, sulfhydryl, hydroxy, nitro, cyano, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy,cycloalkylthio, and heterocycloalkylthio.

“Heteroaryl” refers to a heteroaromatic system comprising 1 to 4heteroatoms and 5 to 14 ring atoms, wherein the heteroatom comprises O,S and N. The heteroaryl is preferably 6 to 10-membered. The heteroarylis preferably 5 or 6-membered, for example, furanyl, thienyl, pyridyl,pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl,tetrazolyl and the like. The heteroaryl ring can be fused to an aryl,heterocyclyl or cycloalkyl ring, wherein the ring bound to the parentstructure is the heteroaryl ring. The heteroaryl can be optionallysubstituted or unsubstituted. When the heteroaryl is substituted, thesubstituent is preferably one or more groups independently selected fromthe group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio,alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy,cycloalkylthio, heterocycloalkylthio, carbonyl, carboxy, andalkoxycarbonyl.

“Heterocyclyl” refers to a 3 to 20-membered saturated or partiallyunsaturated monocyclic or polycyclic hydrocarbon group having one ormore heteroatoms selected from the group consisting of N, O, andS(O)_(n) (wherein n is an integer of 0 to 2) as ring atoms, butexcluding —O—O—, —O—S— or —S—S— in the ring, with the remaining ringatoms being carbon atoms. Preferably, the heterocyclyl has 3 to 12 ringatoms wherein 1 to 4 atoms are heteroatoms, more preferably 3 to 10 ringatoms. Nonlimiting examples of monocyclic heterocyclyl includepyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl,homopiperazinyl and the like. Polycyclic heterocyclyl includes aheterocyclyl having a spiro ring, fused ring or bridged ring.

“Alkoxy” refers to an —O-(alkyl) or an —O-(unsubstituted cycloalkyl)group, wherein the alkyl is as defined above. Nonlimiting examplesinclude methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy and the like. The alkoxy can be optionallysubstituted or unsubstituted. When the alkoxy is substituted, thesubstituent is preferably one or more groups independently selected fromthe group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio,alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy,cycloalkylthio, heterocycloalkylthio, carbonyl, carboxy, andalkoxycarbonyl. “Hydroxy” refers to an —OH group.

“Optional” or “optionally” means that the event or circumstancedescribed subsequently can, but need not, occur, and this descriptionincludes the situation in which the event or circumstance does or doesnot occur. For example, “a heterocyclic group optionally substituted byan alkyl” means that an alkyl group can be, but need not be, present,and this description includes the situation of the heterocyclic groupbeing substituted by an alkyl and the situation of the heterocyclicgroup being not substituted by an alkyl.

Unless otherwise stated, the English abbreviations used in thespecification and claims have the following meanings.

Abbreviations Full name Et₃N Triethylamine DBU1,8-Diazabicyclo[5.4.0]undec-7-ene TMG N,N,N′,N′-tetramethylguanidine PyPyridine DIPEA Diisopropylethylamine NaOMe Sodium methoxide NaOEt Sodiumethoxide NaOtBu Sodium tert-butoxide PCC Pyridinium chlorochromate EEDQ2-Ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline DMACN,N-dimethylacetamide

DETAILED DESCRIPTION OF THE INVENTION

The present invention is described in detail with reference to thefollowing specific examples so that those skilled in the art willunderstand the present invention in a more comprehensive manner. Thespecific examples are used only to illustrate the technical solution ofthe present invention, but are not used to limit the scope of thepresent invention in any way.

Example 1: Preparation of Compound 5

Step 1):

8.0 kg of compound 1, 264 kg of dichloromethane, and 13.0 kg ofanhydrous sodium acetate were added to a 300 L reactor and stirred. Thereaction system was cooled to 0° C. by freezing brine. 17.14 kg of PCCwas then added in batches under nitrogen protection. After thecompletion of the addition, the freeze was stopped, and the reaction wascarried out for 5 h with the temperature rising naturally. After thecompletion of the reaction was determined by TLC detection (ethylacetate:petroleum ether=1:3), the mixture was filtered, and the filtratewas concentrated under reduced pressure to obtain a black oil. Theproduct was eluted over column chromatography (the eluent was ethylacetate:petroleum ether=1:3). The main fraction was collected,concentrated under reduced pressure, and dissolved by addition of 64 kgof ethyl acetate. The solution was washed with 0.5 N dilutedhydrochloric acid solution, water and saturated brine successively,dried over anhydrous sodium sulfate, and concentrated to obtain 6.42 kgof pale yellow oil.

114 kg of dichloromethane and 3.05 kg of 60% sodium hydride were addedto a 300 L reactor and stirred well, and the mixture was cooled byfreezing brine. 7.66 kg of triethyl phosphonoacetate was slowly addeddropwise, and the addition was completed within about 30 min. Themixture was stirred at room temperature until no bubbles were produced.A solution of 6.4 kg of compound 2 obtained in the previous step indichloromethane (85 kg) was added slowly dropwise, and the addition wascompleted within about 1 h. Then the reaction was carried out at roomtemperature for 1.5-2 h. After the completion of the reaction wasdetermined by TLC detection, the mixture was cooled by freezing brine.An aqueous solution of ammonium chloride (1.26 kg of ammonium chloridedissolved in 4.0 kg of water) was added slowly until no bubbles wereproduced. The mixture was stirred for about 0.5 h. Purified water wasthen slowly added dropwise until the mixture was clear. Two phases wereseparated, and the aqueous phase was extracted once withdichloromethane. The organic phases were combined, washed with asaturated aqueous solution of sodium bicarbonate and saturated brine,dried over anhydrous sodium sulfate, and concentrated to obtain a crudeester product. The crude ester product was subjected to columnchromatography (the eluent was ethyl acetate:petroleum ether=1:8). Themain fraction was collected and concentrated to obtain 4.82 kg ofcompound 3, yield: 45.0%. (The TLC condition was petroleum ether:ethylacetate=3:1, the R_(f) of the product=0.7, the R_(f) of the startingmaterial=0.6).

Compound 3: ¹H NMR (400 MHz, CDCl₃) δ=6.85-6.80 (dd, 1H), 5.84-5.80 (d,1H), 4.40 (br, 1H), 4.22-4.17 (q, 2H), 3.42 (s, 2H), 2.08-2.06 (m, 1H),1.89-1.82 (m, 2H), 1.79-1.73 (m, 1H), 1.44 (s, 9H), 1.31-1.27 (t, 3H)ppm.

MS (M+Na): 292.1

Step 2):

4.8 kg of compound 3 and 58.6 kg of formic acid were added to a 100 Lreactor and stirred at room temperature for 15 min. 2.63 kg ofparaformaldehyde was then added, and the mixture was heated to slightlyreflux at 90° C. for 3-4 h until the starting material point disappearedby TLC detection. Most of the formic acid in the reaction solution wasconcentrated (about ⅕ remained), and 1M hydrochloric acid was added toadjust the pH to 1.0. The mixture was washed with ethyl acetate. Theaqueous phase was further added with a saturated aqueous solution ofpotassium carbonate to adjust the pH to 8.0, and extracted with ethylacetate. The organic phases were combined, washed with a saturatedaqueous solution of sodium chloride, dried over anhydrous sodiumsulfate, and filtered. The filtrate was concentrated to obtain 2.42 kgof compound 4, yield: 73.5%.

Compound 4: ¹H NMR (400 MHz, CDCl₃) δ=6.85-6.80 (dd, 1H), 5.96-5.92 (d,1H), 4.22-4.17 (q, 2H), 3.15-3.10 (m, 1H), 2.76-2.70 (m, 1H), 2.28 (s,3H), 2.28-2.21 (m, 1H), 2.04-1.98 (m, 1H), 1.91-1.84 (m, 1H), 1.82-1.74(m, 1H), 1.72-1.65 (m, 1H) ppm.

MS (M+1): 184.2

Step 3):

2.4 kg of compound 4 and then 5.9 kg of methanol were added to a 20 Lreaction flask. 1.49 kg of potassium hydroxide was added in batches at acontrolled temperature no more than 30° C., the addition was completedwithin about 1.5 h, and then the reaction was carried out at 30° C. for2 h. After the completion of the reaction was determined by TLCdetection, the pH was adjusted to 4-5 with 4N hydrochloric acid inmethanol in an ice bath. The mixture was filtered, the filtrate wasconcentrated to dryness, and 2.7 kg of acetonitrile was added understirring to precipitate a crystal. The mixture was filtered and dried toobtain 1.06 kg of compound 5, yield: 52.1%.

Compound 5: ¹H NMR (400 MHz, d⁶DMSO) δ=12.60 (s, 1H), 11.72 (s, 1H),6.94-6.88 (dd, 1H), 6.21-6.17 (d, 1H), 4.00 (s, 1H), 3.57 (s, 1H), 3.07(s, 1H), 2.67 (s, 3H), 2.28-2.20 (m, 1H), 2.02-1.99 (m, 2H), 1.92-1.82(m, 1H) ppm.

MS (M+1): 156.1

Example 2: Preparation of the Compound of Formula I

1.0 kg of compound 5 and 9.4 kg of acetonitrile were added to a 20 Lreaction flask, and then 30 g of N,N-dimethylformamide was addeddropwise. 630 g of oxalyl chloride was slowly added dropwise in an icebath. After the completion of the addition, the mixture was stirred at20° C. for 5 h. A small amount of solid remained at the bottom of thereaction solution, and the reaction solution was directly used in thefollowing condensation reaction without treatment.

1.15 kg of compound VII was dissolved in 7.2 kg of N-methylpyrrolidoneand stirred for 10 min. The previous reaction solution was addeddropwise in an ice bath, and the reaction was stirred at roomtemperature overnight. After the completion of the reaction wasdetermined by TLC detection, the reaction solution was poured into warmwater (45.0 kg) at about 40° C., and 10% sodium hydroxide solution wasslowly added under stirring to adjust the pH to 10. The mixture wasfiltered to obtain a yellow solid.

The resulting filter cake was pulped with warm water (about 5.0 kg) at40° C., and then filtered. The filter cake was dissolved indichloromethane to remove water, dried, concentrated, and purified bycolumn chromatography with gradient elution, the starting eluent wasdichloromethane:methanol=25:1, and finally increased to 15:1. The mainfraction was collected and concentrated to obtain 1.12 kg of thecompound of formula I, yield: 74.5%, with the HPLC purity of 99.71%.

Compound of formula I: ¹H NMR (400 MHz, CDCl₃) δ=9.20 (s, 1H), 8.59-8.58(t, 1H), 8.40 (s, 1H), 8.07-8.03 (d, 2H), 7.77-7.32 (m, 1H), 7.63-7.62(d, 1H), 7.25-7.23 (q, 1H), 7.14 (s, 1H), 7.111-7.106 (d, 1H), 6.97-6.92(q, 1H), 6.86-6.83 (q, 1H), 6.79-6.76 (q, 1H), 6.17-6.14 (d, 1H), 5.21(s, 2H), 4.23-4.18 (q, 2H), 3.16-3.12 (m, 1H), 2.84-2.82 (d, 1H),2.30-2.27 (t, 4H), 2.06-1.99 (m, 1H), 1.90-1.85 (m, 1H), 1.83-1.72 (m,1H), 1.68-1.60 (m, 1H), 1.54-1.52 (t, 3H) ppm.

MS (M+1): 583.2

Example 3: Preparation of the Compound of Formula I

2.0 kg of the compound of formula VII was dissolved in 20 L ofN-methylpyrrolidone in a 50 L reactor. 1.2 kg of compound 5 and then 1.7kg of EEDQ were added, and the reaction was stirred for 14-17 h at acontrolled temperature of 20-25° C. 2.5 kg of water was slowly added inan ice bath, and the pH was adjusted to 9-10 with 5% aqueous NaOHsolution (about 25 L). The mixture was filtered to obtain a product witha wet weight of about 4.9 kg. The resulting yellow solid was added with30 kg of water, and 1 M HCl solution was added dropwise under stirringto adjust the pH to 2-5. The mixture was stirred until it was clear. Themixture was extracted with dichloromethane, the pH of the aqueous phasewas adjusted to 9-10 with 5% aqueous NaOH solution, and the resultingsolid was filtered to obtain a product with a wet weight of about 5.2kg. 88.4 kg of ethanol and 8.8 kg of acetone were added, and the mixturewas heated to reflux until it was clear. The solution was cooled to roomtemperature under stirring to precipitate a crystal for 15 h. Themixture was filtered, and the filter cake was washed with ethanol toobtain 2.1 kg of the compound of formula I as a pale yellow solid,yield: 80.3%, with the HPLC purity of 99.68%.

Since the present invention has been described based on the specificembodiments thereof, some modifications and equivalent variations areapparent to those skilled in the art and are within the scope of thepresent invention.

What is claimed is:
 1. A method for preparing a compound of formula IIor a pharmaceutically acceptable salt thereof,

the method comprising reacting a compound of formula IV with a compoundof formula III, wherein: R is hydroxy, and the method comprises reactingthe compound of formula IV with the compound of formula III in thepresence of a condensing agent, wherein the condensing agent is at leastone selected from the group consisting of DCC, EDC, BOP, HBTU, and EEDQ;wherein the compound of formula II is a compound of formula I, thecompound of formula III is a compound of formula VII, and the compoundof formula IV is a compound of formula VI,

wherein R₂ is selected from the group consisting of an amino protectinggroup and alkyl; or wherein the compound of formula II is Neratinib, thecompound of formula III is a compound of formula VII, and the compoundof formula IV is a compound of formula IX,

wherein R₂ and R₃ are each independently selected from the groupconsisting of an amino protecting group and alkyl.
 2. The method forpreparing the compound of formula II or the pharmaceutically acceptablesalt thereof according to claim 1, wherein a solvent used in the methodis at least one selected from the group consisting of pyridine,quinoline, acetonitrile, N-methylpyrrolidone, dichloromethane, ethylacetate, tetrahydrofuran, N,N-dimethylformamide, andN,N-dimethylacetamide.
 3. The method for preparing the compound offormula II or the pharmaceutically acceptable salt thereof according toclaim 1, wherein the pharmaceutically acceptable salt of the compound offormula I is selected from the group consisting of p- p-toluenesulfonatesalt, methanesulfonate salt, maleate salt, succinate salt and malatesalt.
 4. The method for preparing the compound of formula II or thepharmaceutically acceptable salt thereof according to claim 1, whereinthe condensing agent is EEDQ.
 5. The method for preparing the compoundof formula II or the pharmaceutically acceptable salt thereof accordingto claim 2, wherein the solvent is N-methylpyrrolidone.
 6. The methodfor preparing the compound of formula II or the pharmaceuticallyacceptable salt thereof according to claim 3, wherein thepharmaceutically acceptable salt of the compound of formula I is maleatesalt.
 7. The method for preparing the compound of formula II or thepharmaceutically acceptable salt thereof according to claim 3, whereinthe pharmaceutically acceptable salt of the compound of formula I isdimaleate salt.